Type II diabetes is a syndrome characterized by resistance to insulin and relative insulin deficiency. While some patients can be managed and euglycemia achieved with oral hypoglycemic agents (OHA's) alone, others require insulin. However, despite the use of large doses of insulin, the results of insulin therapy alone are frequently unsatisfactory. The addition of an OHA to the treatment regimen of such patients has been suggested as a method of enhancing insulin action and improving glycemic control. OHA's improve glycemic control, at least acutely, through stimulation of endogenous insulin secretion. This endogenous insulin secretion is potentially important in the control of hepatic glucose output. However, previous studies of combination therapy have demonstrated that fasting hyperglycemia can be improved significantly while post- prandial hyperglycemia remains a problem. Lispro, a fast-acting insulin which provides high serum insulin levels with a short duration of action, may lower glucose excursions during and after meals, and, in combination with OHA's, may further enhance glycemic control. Therefore, it is possible that by reducing the post- prandial burden on endogenous insulin secretory capacity, more insulin may be available and the ability to regulate fasting plasma glucose may be improved. In this study we performed an open-label randomized cross- over study of insulin lispro and sulfonylurea vs. sulfonylurea alone in 22 patients with type II diabetes mellitus who were poorly controlled on a maximum dose sulfonylurea (HbA1c > 8% or two fasting plasma glucoses (FPG) > 160mg/dl). In both arms patients were maintained on the maximum dose of the sulfonylurea used at study entry. Lispro was administered before meals (three times daily) at a dose individual to patient needs. Patients were evaluated at the end of each four month treatment arm, including HbA1c and fasting post-prandial plasma glucose and C-peptide following a standard breakfast of Ensure Plus. Compared to sulfonylurea treatment, combined therapy produced reductions in FPG (154 vs. 193mg/dl, p < .0001) and two hour post-prandial plasma glucose (251 vs. 331mg/dl, p < .001). Combined therapy also reduced HbA1c (7.2% vs. 9.0%, p < .0001). Body weight was slightly higher (209 vs. 202 lb, p < .0001). Treatment had no effects on either fasting or stimulated C-peptide levels. Our findings highlight the importance of correction of post-prandial hyperglycemia. Furthermore, lispro in combination with sulfonylurea therapy can improve glucose control with minimum exposure to exogenous insulin, a potentially important consideration given the concern that hyperinsulinemia has been linked to atherosclerosis. Lispro insulin was officially marketed under the trade name, Humalog, in the fall of 1996. Due to its outstanding safety and efficacy profile, we are anticipating further research in the near future utilizing lispro in combination with other glucose lowering drugs.